Autoimmune diseases represent a major health care problem and constitute the core of the clinical practice of Rheumatology. Although substantial progress has been made over the last decades, we still lack a precise understanding of the mechanisms responsible for the apparent failure of the immune system that results in autoimmunity. Recent advances in basic immunology, brought about the introduction into the field of the modern tools of molecular biology, have opened up new avenues to investigate autoimmunity. The overall objective of the research proposed in this Program Project is to investigate pathogenetic mechanisms of systemic autoimmune diseases and specifically rheumatologic diseases. To accomplish this goal the Program Project has been organized into five projects, supported by an administrative core unit. All five projects relate directly to the central theme of the research. Projects I and II focus on the autoantibody response in R.A. Collectively, they will investigate genetic and environmental factors underlying the sustained autoimmune response in this disease. Projects III and IV focus on mechanisms of abnormal T cell receptor repertoire development in animal models of autoimmunity. Project V will investigate contributions of the complement system to effector pathogenetic mechanisms of autoimmune diseases. Many collaborative arrangements have been established among the investigators of the five projects. Perhaps more important are the close conceptual relationships both explicit and implicit in the research proposed by the participating investigators.